A single-cell resolved genotype-phenotype map using genome-wide genetic and environmental perturbations

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  • dc.contributor.author Nadal-Ribelles, Mariona
  • dc.contributor.author Solé, Carme
  • dc.contributor.author Díez Villanueva, Pablo
  • dc.contributor.author Stephan-Otto Attolini, Camille
  • dc.contributor.author Matas, Yaima
  • dc.contributor.author Steinmetz, Lars M.
  • dc.contributor.author Nadal Clanchet, Eulàlia de
  • dc.contributor.author Posas Garriga, Francesc
  • dc.date.accessioned 2025-05-08T06:01:40Z
  • dc.date.available 2025-05-08T06:01:40Z
  • dc.date.issued 2025
  • dc.description.abstract Heterogeneity is inherent to living organisms and it determines cell fate and phenotypic variability. Despite its ubiquity, the underlying molecular mechanisms and the genetic basis linking genotype to-phenotype heterogeneity remain a central challenge. Here we construct a yeast knockout library with a clone and genotype RNA barcoding structure suitable for genome-scale analyses to generate a high-resolution single-cell yeast transcriptome atlas of 3500 mutants under control and stress conditions. We find that transcriptional heterogeneity reflects the coordinated expression of specific gene programs, generating a continuous of cell states that can be responsive to external insults. Cell state plasticity can be genetically modulated with mutants that act as state attractors and disruption of state homeostasis results in decreased adaptive fitness. Leveraging on intra-genetic variability, we establish that regulators of transcriptional heterogeneity are functionally diverse and influenced by the environment. Our multimodal perturbation-based single-cell Genotype-to-Transcriptome Atlas in yeast provides insights into organism-level responses.
  • dc.description.sponsorship This work was founded by MICIU/AEI /10.13039/501100011033 and ERDF/EU to FP and EdN (PID2021-124723NB-C21/C22). Funding from the Ministry of Science, Innovation and Universities through the Centres of Excellence Severo Ochoa Award, and from the CERCA Programme of the Government of Catalonia and the Unidad de Excelencia María de Maeztu, funded by the AEI (CEX2018-000792-M). The Ramon y Cajal Program (Spanish Ministry of Science, RYC2021-033520-I) and La Caixa Junior (LCF/BQ/PR20/11770001) awarded to MNR. FP and EdeN are recipients of an ICREA Acadèmia award (Government of Catalonia).
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Nadal-Ribelles M, Solé C, Díez-Villanueva A, Stephan-Otto Attolini C, Matas Y, Steinmetz L, et al. A single-cell resolved genotype-phenotype map using genome-wide genetic and environmental perturbations. Nat Commun. 2025 Mar 18;16(1):2645. DOI: 10.1038/s41467-025-57600-4
  • dc.identifier.doi http://dx.doi.org/10.1038/s41467-025-57600-4
  • dc.identifier.issn 2041-1723
  • dc.identifier.uri http://hdl.handle.net/10230/70326
  • dc.language.iso eng
  • dc.publisher Nature Research
  • dc.relation.ispartof Nat Commun. 2025 Mar 18;16(1):2645
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2021-124723NB-C21
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2021-124723NB-C22
  • dc.rights © The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by/4.0/
  • dc.subject.keyword Gene expression
  • dc.subject.keyword Gene expression analysis
  • dc.subject.keyword Transcriptomics
  • dc.title A single-cell resolved genotype-phenotype map using genome-wide genetic and environmental perturbations
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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